The principal objective of these studies is to delineate the significance of immune responses within the central nervous system (CNS) of mouse strains which vary in their resistance to the neurotropic street rabies virus (SRV). Anti-SRV neutralizing antibody was not detected in the cerebrospinal fluid (CSF) of resistant or susceptible mice for the first 10 days postinoculation. It was initially detected in the highly resistant-asymptomatic SJL and CBA mice after the 15th day. Neutralizing antibody was not detected in the CSF of mice with serum neutralizing antibody titers of less than 1:320. Nonetheless, anti-SRV neutralizing antibody in the CSF might have been important in resolving infections of mice which survived following development of clinical CNS disease. It appeared in high titer in both DBA/2 and BALB/c strains during their recuperation period (greater than 10 days postinoculation), and was not present in sick susceptible A.SW/Sn mice which were alive 12 days after SRV inoculation, but were destined to die. Direct infection of the CNS via intranasal (IN) challenge has shown that anti-SRV neutralizing antibody in the CSF is inconsequential in genetic resistance or CNS immunity to SRV. In contrast, serum neutralizing antibody was essential in both instances since SJL mice with this antibody, but without CSF antibody (5-7 days postinoculation) did not die when challenged IN. In contrast, mice with neither serum nor CSF antibody (1-3 days postinoculation) died. Studies with nude mice, which make a minimal neutralizing antibody response to SRV, have shown that SRV was not present in the CSF of mice which had brain and spinal cord virus titers exceeding one hundred thousand MICLD 50/0.03 ml.